Faculty of Medicine, Dentistry & Health Science Department of Biochemistry and Molecular Biology

Terry Mulhern

Signal transduction and human diseases: Linking protein structure, function and biology

  • We study the structure and function of proteins, in particular kinases and phosphatases, which are the enzymes that catalyze the attachment and removal of phosphate groups.
  • Phosphorylation acts to switch on and off a variety of cellular responses including: motility, proliferation and programmed cell death.
  • Loss of control of these functions leads to cancer and other diseases.
  • We employ a multidisciplinary approach that includes biophysics, biochemistry, and molecular and cellular biology
Diagram of the domain structure of Src-family protein tyrosine kinases
A schematic representation of the domain structure of Src-family protein tyrosine kinases: the phosphorylation sites that control catalytic activity are indicated

Understanding protein structure and function

Signal transduction is a complex web of molecular recognition events and activation-deactivation steps that use molecular switches such as phosphorylation and conformational change. When signal transduction goes wrong, disease states such as diabetes and cancer can result. Our research projects are focused on learning about how defects in signal transduction lead to human diseases. The projects use recombinant DNA manipulation, protein expression and purification, activity and binding assays as well as biophysical analyses including fluorescence spectroscopy, circular dichroism (CD), analytical ultracentrifugation, calorimetry, protein crystallography, small angle x-ray (SAXS) and neutron scattering (SANS) and, in particular, nuclear magnetic resonance (NMR) spectroscopy.

The study of protein structure and interactions by NMR

NMR spectroscopy provides a window into molecular structure, interactions and dynamics at an atomic level. There have been some spectacular developments in NMR techniques in recent years, which have allowed us to determine the 3-dimensional solution structure of biologically important molecules of ever increasing size and complexity. NMR also provides techniques for studying protein dynamics and the interaction between biopolymers, be they protein or nucleic acids, and their ligand partners in solution. These features have made NMR spectroscopy a key discipline in many areas of biomedical research and the pharmaceutical industry. Researchers in my group have access to 400, 500 and 600 MHz spectrometers (with 800 MHz coming online in 2005). Associate Professor Paul Gooley leads another NMR group in the Department giving us critical mass in areas such as pulse sequence development, isotopic labelling, triple-resonance spectroscopy and protein structure calculation.Data from NMR spectroscopy
Data from nuclear magnetic resonance (NMR) spectroscopy to determine the atomic resolution structure of proteins

Current research projects

(In collaboration with Dr Heung-Chin Cheng)
  • Phosphorylation-dependent and -independent control the proto-oncogenic Src-family of protein tyrosine kinases
  • Functional regulation of the upstream kinases (CSK and CHK) that inactivate Src-family kinases in vivo
  • Structure-function relationships controlling the activity and subcellular localization of the tumour suppressor phosphatase PTEN
(In collaboration with Assoc Prof Trevor Lithgow)
  • Structure of the TOM complex: the Translocase of the Outer Mitochondrial Membrane
NMR structure of the SH2 domain of CHK
The NMR structure of the SH2 domain of the CSK homologous kinase (CHK)
small angle scattering data Diagram showing amino acid residues in active site of PTEN
Small angle scattering data can also be used to define the shape of proteins in solutionAmino acid residues in the active site of the tumour suppressor phosphatase PTEN

Lab personnel

Head

Dr Terry Mulhern

Research staff

Dr Romana Kristelly (Research Officer)
Theresa Wenli Qiu (Research Assistant)

Graduate students

Megan Bird
Natalie Gunn
Sevgi Irtegun
Ryan Mills

Honours students

Simon Maaser
Alex Rey

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